长周期低剂量下二苯甲酮衍生物对鱼类毒性与毒理机制研究

Benzophenone derived compounds are a class of important environemental pollutants with different structure. Recently, they are wildsperd and high concentration in aquatic environment. Moreover, it is not enough data of their toxicity. In addition, thire biotransormation and toxicological mechanism in vivo are not well documented. Therfore, in this project, benzophenone derived compounds with different structure were selected as goal chemicals. The biological activies will be determined using a group in vitro test. Chinese rare minnow and medaka with different life cycle will be exposed to benzophenone derived compounds with different structure during short term or life cycle. These biomarkers from moclecule to indicidual level in fish were determined. Moreover, the relation between concentration and effect about biomarker were also determined. According these results, toxicity of benzophenone derived compounds will be discovered, and, these effects of benzophenone derived compounds were compared. The bioaccumulation and biotransformation of these compunds with different structure in vivo will be detected basing on chemical analysis. The effects of key pathway were analyzed using high throughput sequencing. The molecular targets and regulation process of key pathway were disvoved by RNAi and RT-PCR etc. The toxicological mechanism of low concentrations benzophenone derived compounds on fish during long-term exposure were explored, according to the effects of key pathway, biotransformation, and change of biomarkers were integrated. This project will provide the molecular toxicological base for assessment in their environemtal hazards and risk. In addiion, they will provied new technology and idea for chemical mangement in China.

二苯甲酮衍生物是一类具有不同结构类型的重点环境关注污染物。目前研究发现其环境分布广、浓度水平高、毒性数据不足，且体内生物转化及毒性作用机制不清晰。本项目以不同结构类型的二苯基酮衍生物为研究对象，利用自主构建成组体外测试技术筛选其生物效应，选择稀有鮈鲫与青鳉作为实验生物，采用短期暴露与长周期暴露相结合，分析从不同层次生物标志物的剂量响应关系，确认其毒性效应，探索其不同结构的效应差异。利用高灵敏分析手段，阐明不同结构类型的二苯酮衍生物在鱼类富集潜力和代谢转化过程。基于高通量测序技术，分析关键作用通路的响应，采用RNA干扰等新分子生物学手段，阐明其分子作用位点与通路调控过程；综合体内转化过程与多层次指标响应分析，探索其对鱼类长周期低剂量下的毒性作用机制，为二苯甲酮衍生物的环境危害与风险管理提供分子毒理学基础，也为我国化学品管理提供评估新技术手段和研究思路。

二苯甲酮衍生物是一类具有不同结构类型的重点环境关注污染物。本项目以不同结构类型的二苯基酮衍生物为研究对象，通过其与核受体蛋白的分子对接技术筛选其生物效应，选择稀有鮈鲫与青鳉作为实验生物，采用短期暴露与长周期暴露相结合，从不同层次生物标志物的剂量响应关系分析，结果表明二苯甲酮类衍生物不仅具有繁殖和发育毒性，同时具有内分泌干扰效应；其繁殖毒性与取代基有关，羟基越多，效应越高。通过高通量测序技术，筛选出二苯甲酮衍生物改变DNA损伤相关的信号通路，其作用机制是BP、BP-1和BP-4引起雄鱼肝脏发生DNA氧化损伤，进而抑制DNA修复，抑制细胞周期，最终诱导细胞发生凋亡。为二苯甲酮衍生物的环境危害与风险管理提供分子毒理学基础，也为我国化学品管理提供评估新技术手段和研究思路。